Pharmaceutical compositions containing 1-benzoyl-3,5-dimethyl pyrazole in the treatment of inflammation

ABSTRACT

PHARMACEUTICAL COMPOSITION CONTAINING THERAPEUTICALLY ACTIVE 1-BENZOYL 3,5-DIMETHYL PYRAZOLE USED IN TOPICAL APPLICATIONS, IN THE TREATMENT AND THE PREVENTION OF PAIN AND INFLAMMATION OF SKIN, CONNECTIVE TISSUE OR JOINTS.

United States Patent Office 3,743,739 Patented July 3, 1973 U.S. Cl.424-273 3 Claims ABSTRACT OF THE DISCLOSURE Pharmaceutical compositioncontaining therapeutically active l-benzoyl 3,5-dimethyl pyrazole usedin topical applications, in the treatment and the prevention of pain andinflammation of skin, connective tissue or joints.

The present invention provides pharmaceutical preparations containing asactive ingredient 1-benzoyl-3,5-dimethyl pyrazole of Formula I:

OHa

optionally together with pharmaceutically suitable carriers or withother active principles.

The compound of Formula I is known and may be prepared by a method knownper se which comprises reacting 3,5-dimethyl pyrazole with benzoylchloride in the presence of triethylamine and ether.

It has now been found that the compound of Formula I, used in topicalapplication, possesses valuable pharmacological and therapeuticproperties, especially analgesic, antiinflammatory and antirheumaticproperties; it protects from UV rays and facilitates the penetration ofother suitable medicines through intact animal or human skin.

The toxicity of l-benzoyl-3,5-dimethyl pyrazole is very weak and the LDin mice, is 2000 mg./kg. per

The analgesic activity was studied in mice by the hot plate method[Arch. Int. Pharm. 107, 322 (1956)]. The application of the compound ismade by massage of the four paws, for one minute, before the passage onthe hot plate at 56 C. It was observed that the reaction time increasesof about 50%, 30 to 60 minutes after the treatment.

A very important analgesic activity was also demonstrated for thiscompound by the method of arthralgia provoked by silver nitrate [LaBelle, A., Tislow, R., J. of Pharm. 98, 19 (1950)]. The massage of thejoint with the compound for one minute decreases, of from 50 to 75% thenumber of the rats cries.

The antiinfiammatory activity was studied on the rats ear oedemaprovoked by croton oil [Tonelli, G., et al. Endocrin. 77, 625 (1965),modified by Le Douarec, J. C., et al., J. Pharmacol. 1,395 (1970)].

The topical administration of a solution, containing 100 mg./ml. of thecompound, inhibits of from 35 to 40% the inflammation provoked by a 2%croton oil.

An important antiinfiammatory activity was also evidenced on the UVerythema in the guinea-pig. When the product is administered, after theUV irradiation, in the form of an alcoholic solution or an ointment at 5to 20% of the active ingredient, the erythema decreases of from 38 to65% in comparison with the untreated animals.

A protective eitect against the UV irradiation was also noted when theproduct is administered 15 minutes before the exposition of the animalto the rays. As a matter of fact, a solution at 10% of 1benzoyl-3,5dimethyl pyrazole inhibits of the appearance of erythema.

This product also possesses an antilipolytic activity; especially, atthe doses of 5 to 50 mg./ kg. per os, there has been observed, in therat, a decrease of from 50 to 80% of the free fatty acids and of from 8to 12% of the plasmatic triglycerides, while the hepatic triglyceridesincrease up to 150% and the plasmatic corticosterone increases of from57 to 62%.

The low toxicity and the here-above described properties enable the useof l-benzoyl-3,5-dimethyl pyrazole in therapy, especially in thetreatment and the prevention of pain and inflammation of skin,connective tissue or joints, such for example, dermatitis, erythema,arthritis.

The product may be administered preferably topically in variouspharmaceutical forms, such for example, as lotions, creams, ointments orsprays, optionally together with suitable pharmaceutical carriers suchfor xample, as distilled water, alcohol, lanolin, propyleneglycolstearate or propellants, or with other active principles.

The concentration in active ingredient may be within the range of from 5to 50%, preferably of from 10 to 25%, for 2 to 5 applications a day.

The following examples illustrate the process for preparing1-benzoyl-3,5-dimethyl pyrazole and pharmaceutical compositions thereof.

EXAMPLE 1 A solution of 105.3 g. of benzoyl chloride in 300 ml. ofanhydrous ether was added dropwise to a solution of 72 g. of3,5-dimethyl pyrazole and 76 g. of triethylamine in 2400 ml. ofanhydrous ether.

The so-obtained suspension was refluxed for one hour, then cooled andtaken up with 1000 m1. of water. The organic layer was washed first withml. of a normal hydrochloric acid solution then with 200 ml. of water.

After drying, concentration, then distillation of the residue, therewere obtained g. of l-benzoyl-3,5-di- Distilled water, q.s.p. 100 g.

3 EXAMPLE 4 Cream G. 1-benzoy1-3,5-dimethyl pyrazole 20 Propyleneglycolstearate Fluid lanolin 2 Methyl paraoxybenzoate 0.15 Propylparaoxybenzoate 0.05 Distilled water, q.s.p. 100 g.

EXAMPLE 5 Spray G. 1-benzoyl-3,5-dimethy1pyrazole 20 15 Ethylic alcohol5 Polyoxyethylenated oleic ether 1 Fluid propellant: Freon 11/12(50-50%) 74 We claim:

1. A method of treating a living animal or human body affiicted withinflammation of the skin connective tissue or joints, which comprisesadministering to said body an antiinflammatorily effective amount ofl-benzoyl 3,5-dimethyl pyrazole with a pharmaceutically acceptablecarrier.

2. A method as claimed in claim 1 wherein the amount of l-benzoyl3,5-dimethyl pyrazole is comprised between 5 and 50% by Weight.

3. A method as claimed in claim 1 wherein the carrier is in the form ofa lotion, ointment, cream or spray.

References Cited Chem. Abstract, Seventh Collective Subject Index. P Sn,p. 19070.

STANLEY J. FRIEDMAN, Primary Examiner 1 UNITED STATES PATENT OFFICECERTIFICATE OF CORRECT ION P t n 3.7 5.759 Dated July 5. 1975),lean=nlm1d T.eDOuaI'eC. Laszlo Beregil Pierre Hugon It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 1, line 30,- d elete the formula as shown, insert Y the followingformula:

Column 4, lines 5 and 9, after the word "benzoyl",

insert a "hyphen" signed'and sealed this 7th day of January 1975.

(SEAL) 'Attest: I

v v k I V i 3' l. GIBSON C. .QTRS IALL 1.1.x I zi gzting OfficerCommissioner of intents USCOMM-DC 60376-969 FoRia PO-IOSO (10-59) v UT.VE-III" "INTI" OFFICE I "'I 0-Sl-I3l

